Lymphocytes and hematopoietic cells of the myelomonocytic lineage reciprocally interact during differentiation and in their roles as regulatory and effector cells of adaptive and non-adaptive immunity. Lymphocyte products, or lymphokines, are particularly important in regulating activation and function of phagocytic cells of the myelomonocytic lineage during immune response or inflammation. Lymphokines also have a regulatory role on proliferation, differentiation, and functional activity of cells of the myelomonocytic lineage at different stages of differentiation, from the precursor to the terminally differentiated cells. Although these effects have been determined in vitro or in vivo in pathologic situations, it is likely that the effects observed in pathology are an exaggeration of the physiologic role played by lymphocytes and their products in regulation of the homeostasis of the hematopoietic system. The long range objective of this project is to identify and investigate the mechanisms of interaction between lymphocytes and myelomonocytic cells. Part of our studies are performed using in vitro established human myeloid cell lines as a model system of differentiation in which regulation by lymphokines of differentiation-associated markers is analyzed at phenotypic and molecular levels. The study will be focused on the investigation of the molecular mechanisms by which tumor necrosis factor and interferon- gamma act synergistically in inducing monocytic differentiation in immature myeloid cells. The modulating effects of other lymphokines will also by analyzed. Among other markers of differentiation, the maturation of the NADPH oxidase system and respiratory burst capabilities during normal and lymphokine-induced myelomonocytic cell differentiation will be investigated. The information obtained in these model systems is then applied to the study of normal and leukemic cells, in order to understand how differentiation and maturation are regulated in physiologic conditions and their alteration in malignant myelomonocytic cells.